This application focuses on the role of novel molecules, the matrix metalloproteinases (MMPs), in relapse to cocaine and methamphetamine (Meth). MMPs are a family of enzymes that regulate the extracellular matrix (ECM) and cell-adhesion proteins, and very recently have been shown to be involved in spatial memory formation. Underlying drug addiction are persistent memories of the drug that are believed to produce craving and relapse. Drug taking behavior itself involves the consolidation of a drug memory. With each drug use, the memory may be reactivated (retrieved) and subsequently reconsolidated to maintain the original memory. During reactivation, the memory is thought to be labile and susceptible to disruption. Therefore, molecules involved in plasticity should influence reconsolidation. Based on our preliminary data and several studies outside the field of drug abuse, we propose that formation of the original memory (consolidation) as well as reconsolidation processes require shifts in MMP-mediated events. Recent work has demonstrated that activity of the enzymes MMP-3 and MMP-9 in the hippocampus is correlated with learning a spatial water maze task. Further, intracerebral ventricular (i.c.v.) injection of an MMP inhibitor (FN-439) suppresses this spatial learning. Studies in our laboratory have extended these findings to cocaine-induced conditioned place preference (CPP) behavior. Inhibition of MMPs significantly attenuates the acquisition of CPP and blocks reconsolidation of the cocaine memory. In this application we wish to expound on these findings. We will test the central hypothesis that MMPs are critical for reconsolidation of the drug memory such that this memory can be disrupted or diminished with MMP inhibitors during cocaine- and Meth-primed reinstatement. Specifically, we wish to test 1) whether MMP inhibitors can diminish cocaine-primed reinstatement of self-administration in a reactivation-dependent manner, and 2) whether MMP inhibitors can also diminish Meth-primed reinstatement in a reactivation-dependent. The ultimate significance of these studies is to determine whether an MMP inhibitor can disrupt the memory for cocaine or Meth in a reactivation-dependent manner thus providing a novel treatment for treating drug addiction. [unreadable] [unreadable] [unreadable]